The growing populations of the elderly and those with type-II diabetes are at high risk for developing chronic wounds that are slow to heal. Effective therapeutics to promote wound healing can significantly improve the lives of those faced with chronic wounds as well as injured military personnel and others with acute wounds. Somagenics has developed an RNAi-based therapeutic platform, short shRNA (sshRNA), which, when formulated for effective liver delivery, generated very promising preclinical data for the company's lead therapeutic program of hepatitis C. Here we propose the development of an sshRNA therapeutic strategy to accelerating wound healing. The approach involves down-regulating a protein that regulates multiple factors including the synthesis of heat shock proteins, which are known to accelerate wound healing by promoting angiogenesis, vasculogenesis, and macrophage recruitment. Intervention with a separate target is expected to enhance keratinocyte growth and motility, two processes critical for wound closure. The goal of Phase I is to identify and validate a pair of chemically-modified oligonucleotide agents that are effective in inhibiting these respective targets and produce downstream effects beneficial to wound healing in tissue culture models. For Phase II, we plan to use a well-established murine wound-healing model to test the in vivo efficacy of these inhibitors under various formulations. PUBLIC HEALTH RELEVANCE: Therapeutics that promote rapid wound closure and healing and reduce the risk of infection would benefit both military and civilian populations. In this regard, the oligonucleotide-based therapeutics that we are planning to develop have advantages: they are stable and do not require refrigeration, they are expected to be active in different formulations, and they can produce long-lasting therapeutic effects. These inhibitors should provide a significant heath impact by targeting wounds in both military and civilian populations, including chronic wounds, pressure ulcers, venous ulcers, and especially diabetic ulcers, for which there is enormous medical need and potential for savings in healthcare costs